Benzphetamine hydrochloride of formula (I), chemically known as (2S)-N-benzyl-N-methyl-1-phenylpropan-2-amine is an amphetamine derivative exhibiting appetite suppressant activity and is utilized for long term management of obesity under the brand name Didrex. The drug was first synthesized by Heinzelman et.al. (U.S. Pat. No. 2,789,138) and found to be a superior bronchodilator and a CNS stimulator, which increases heart rate and blood pressure.

U.S. Pat. No. 2,789,138 discloses a method for preparation of benzphetamine hydrochloride (I) by reaction of benzyl chloride with dextromethamphetamine (d-desoxyephedrine) in the presence of a base such as sodium carbonate and in an inert organic solvent such as benzene, toluene, xylene etc. The preliminary effort for preparing the hydrochloride salt comprised of dissolving the benzphetamine free base of formula (II) in ethyl acetate followed by treatment with ethanolic hydrogen chloride. However, the hydrochloride salt thus formed was reported to have a melting point of 129° C. to 130° C. The document does not mention either the yield or the purity of the final product thus obtained. Current literature however indicates that benzphetamine has a melting point between 152° C. and 153° C. (Merck Index, 10th edition). The higher melting point reported in current literature suggests that the product thus obtained was highly impure and required several purifications which would eventually reduce the final yield and was thus not suitable for commercial scale.
U.S. Pat. No. 5,536,877 discloses a process for preparation of aryl benzyl amines by reaction of aryl amines with benzyl chloride in the presence of an inorganic base and a phase transfer catalyst like tetrabutylammonium chloride. The reaction was carried out at an elevated temperature range of 90° C. to 110° C. with the reaction time of about 24 hours which is abnormally long even in the presence of a phase transfer catalyst. Further, there was no disclosure about the isolation method or the yield or purity of the final product.
U.S. Pat. No. 7,456,318 discloses a process for preparation of benzphetamine by reaction of an excess of methamphetamine with benzyl chloride. Methamphetamine was employed in a molar ratio of 2:1 with respect to benzyl halide for scavenging the by-product hydrogen halide formed during the reaction. Further, due to the precipitation of the hydrogen halide salt of methamphetamine during the reaction, the reaction mixture became too viscous for effective agitation and had to be diluted with a solvent such as toluene. The hydrogen halide salt of the reactant also had to be separated before allowing the reaction to proceed further.
Benzphetamine (II) obtained during the reaction was then treated with concentrated hydrochloric acid. The hydrochloride salt (I) thus obtained was an oil, which had to be crystallized after azeotropic removal of water and further cooling. It is pertinent to mention that the product of formula (I) thus obtained has about 4.3% of the starting material and required to be purified further for obtaining the desired purity for conforming to regulatory specifications, thereby reducing the overall yield considerably.
A crystallization method for obtaining crystalline benzphetamine hydrochloride is disclosed in U.S. Pat. No. 7,750,187 and comprises addition of benzphetamine hydrochloride usually obtained as oil in an organic solvent such as toluene to form a biphasic mixture, removing water and crystallizing benzphetamine hydrochloride and separating the crystalline benzphetamine hydrochloride from the organic medium. The method utilizes a Dean-Stark apparatus for removal of water. Further, the crude benzphetamine hydrochloride which was obtained as an oil had to be recrystallized from a mixture of ethyl acetate and isopropanol followed by another recrystallization utilizing ethyl acetate, in order to obtain the desired purity. Thus the effective yield for obtaining a crystalline solid from benzphetamine hydrochloride oil was only about 70%. Thus, there was considerable loss during the reprocessing thereby, rendering the method uneconomical and unfeasible for commercial exploitation.
WO 2008048254 also discloses a process for preparation of highly pure crystalline benzphetamine hydrochloride by utilizing ethyl acetate in association with an organic modifier such as ethanol, methanol, isopropanol and n-butanol. The method involved initial crystallization of benzphetamine hydrochloride oil from ethyl acetate followed by further crystallization of the product from a binary mixture of ethyl acetate and an alcohol. The yields obtained herein also were between 55-70%, which was not suitable for commercial scale.
Another method for purification of WO 2006057778 involves removal of the methamphetamine impurity in an aqueous medium having a pH range of 6-8, however herein also the step of obtaining a crystalline product involved azeotropic removal of water with toluene as solvent. The yield obtained was only 70%; thus the method was uneconomical due to the multiple steps of purification and crystallization.
Therefore, to overcome the problems associated with the above prior art methods, there was a need to develop a simple, efficient, high yielding process which requires a short period of time and does not result in unreacted starting material remaining at the end of the reaction, with increased yield and have minimal impurities. Further, there is a need for a process which yields benzphetamine hydrochloride salt of formula (I) as a crystalline solid and not as an oil, without requiring any additional purification steps.